DESCRIPTION: (Applicant's Abstract) The goal of this research project is to study the principles and mechanisms involved in antibody-based therapy for phencyclidine (PCP) abuse. Studies from this laboratory have shown that a murine monoclinal anti-PCP Fab antibody fragment (anti-PCP Fab) is capable of reversing PCP-induced behavioral effects in rats. These studies demonstrate that the anti-PCP Fab is a class-specific antagonist that is effective against several members of the arylcyclohexylamine drug class and that it reverses PCP-induced toxicity in a dose-dependent manner. Also, the anti-PCP Fab dramatically alters the disposition of PCP and produces a rapid redistribution of PCP out of the brain. The next series of experiments will be used to examine the therapy in a large animal model, the dog. These studies will test the hypothesis that the anti-PCP Fab reverses PCP-induced toxicity in a manner that can be predicted by a pharmacokinetic/pharmacodynamic model. Consequently, the pharmacokinetic studies will examine the ability of the anti-PCP Fab to alter the disposition of PCP, and the behavioral studies will investigate the anti-PCP Fab reversal of PCP-induced toxicity. Male and female dogs will be used in these studies to determine if there are any canine sex differences in therapy. Data from the combined pharmacokinetic/ pharmacodynamic models in rats and dogs will be used to scale-up the therapy to humans. Therefore, the data should provide important information for the development of antibody-based therapy for other drugs of abuse.